Mammalian polo-like kinase 1 (PLK1), a major kinase with pivotal roles in multiple aspects of cell division, is closely associated with human cancer development and is frequently overexpressed in various cancers, including prostate cancer (PCa). PLK1 has been postulated to be a proto-oncogene; however, direct evidence to support this notion is still lacking, in part, due to the lack of appropriate animal models. The overall gol of this grant proposal is to delineate the oncogenic roles of PLK1 overexpression in PCa development and metastasis. The hypothesis being tested is that PLK1 functions as a proto-oncogene during PCa initiation, progression, and metastatic dissemination. Our 2 specific aims are: 1) to define the role of PLK1 overexpression in PCa development using our recently established prostate-specific Plk1 transgenic mouse model; and 2) to determine the role of PLK1 overexpression in PCa dissemination by elucidating the molecular mechanisms underlying PLK1-induced epithelial-mesenchymal transition and PCa-cell invasion and defining the pro-metastatic properties of PLK1 using xenograft PCa models and the Plk1 transgenic mouse model. The findings of this work will provide the first in vivo evidence that PLK1 functions as a proto-oncogene in PCa. Furthermore, the results are anticipated to uncover a novel function of PLK1 that goes beyond its canonical role, and to define the oncogenic roles of PLK1 during PCa initiation, progression, and metastatic dissemination. The knowledge gained from this proposed study will fundamentally advance our understanding of the oncogenic functions of PLK1 and the molecular basis of PCa development and metastatic dissemination, which have the potential to facilitate optimization of treatment regimens targeting PLK1 signaling to significantly enhance anticancer efficacy. Furthermore, the ideas behind this proposal may be generalizable to many other cancers since preliminary clinical evidence suggests that PLK1 is involved in the development of several other human cancers.